NM_173615.5:c.647C>T

Variant names:

• chr16-22110952-C-T
• rs149744090
• NM_173615.5:c.647C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_173615.5(VWA3A):​c.647C>T​(p.Ala216Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 1,610,336 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: VWA3A NM_173615.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.444
• Publications: 4 publications found

Genes affected

VWA3A (HGNC:27088): (von Willebrand factor A domain containing 3A) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007252872).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173615.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA3A	NM_173615.5	MANE Select	c.647C>T	p.Ala216Val	missense	Exon 8 of 34	NP_775886.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA3A	ENST00000389398.10	TSL:5 MANE Select	c.647C>T	p.Ala216Val	missense	Exon 8 of 34	ENSP00000374049.5	A6NCI4-1
	VWA3A	ENST00000568328.5	TSL:1	c.647C>T	p.Ala216Val	missense	Exon 8 of 23	ENSP00000457770.1	H3BUS3
	VWA3A	ENST00000877573.1		c.647C>T	p.Ala216Val	missense	Exon 8 of 33	ENSP00000547632.1

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000738 AC: 179 AN: 242602 AF XY: 0.000739

Gnomad AFR exome AF: 0.0000670

Gnomad AMR exome AF: 0.000650

Gnomad ASJ exome AF: 0.00423

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.000900

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000452 AC: 659 AN: 1457998 Hom.: 4 Cov.: 30 AF XY: 0.000446 AC XY: 323 AN XY: 724772

African (AFR) AF: 0.0000299 AC: 1 AN: 33424

American (AMR) AF: 0.000859 AC: 38 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00392 AC: 102 AN: 26050

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39576

South Asian (SAS) AF: 0.000223 AC: 19 AN: 85112

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53138

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.000385 AC: 427 AN: 1110414

Other (OTH) AF: 0.000863 AC: 52 AN: 60258

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74496

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.00170 AC: 26 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000835 Hom.: 2

Bravo AF: 0.000778

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000710 AC: 6

ExAC AF: 0.000727 AC: 88

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.7
DANN	Benign	0.41
DEOGEN2	Benign	0.00080	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.13	N
PhyloP100		0.44
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.050
Sift	Benign	0.066	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.095
MVP		0.014
MPC		0.044
ClinPred		0.0069	T
GERP RS		2.1
Varity_R		0.018
gMVP		0.11
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149744090; hg19: chr16-22122273; COSMIC: COSV107493709; COSMIC: COSV107493709;